Neutrophils play a key role in the elimination of pathogens. They are remarkably short-lived with a circulating half life of 6–8 h and hence are produced at a rate of 5 × 1010–10 × 1010 cells/day. Tight regulation of these cells is vital because they have significant histotoxic capacity and are widely implicated in tissue injury. This review outlines our current understanding of how neutrophils are released from the bone marrow; in particular, the role of the CXC chemokine receptor 4/stromal-derived factor 1 axis, the relative size and role of the freely circulating and marginated (i.e. slowly transiting) pools within the vascular compartment, and the events that result in the uptake and removal of circulating neutrophils. We also review current understanding of how systemic stress and inflammation affect this finely balanced system.

Objective. To verify the hypothesis that in rheu-matoid arthritis (RA), tumor necrosis factor (TNF) plays a critical role in regulating leukocyte trafficking and chemokine levels. Methods. Ten patients with longstanding RA received a single 10 mg/kg infusion of anti-TNF mono-clonal antibody (cA2). The articular localization of autologous granulocytes, separated in vitro and labeled with 111 In, was studied by analysis of gamma-camera images both before and 2 weeks after treatment. At the same sequential time points, synovial biopsy samples were assessed for infiltrating CD3 T cells, CD22 B cells, and CD68 macrophages. Synovial tissue expression of the chemokines interleukin-8 (IL-8), monocyte chemotactic protein 1 (MCP-1), macrophage inflamma-tory protein 1 (MIP-1), MIP-1, Gro, and RANTES was also determined. Serum IL-8 and MCP-1 concentrations were measured by enzyme-linked immunosor-bent assay. Results. Anti-TNF therapy in RA significantly reduced 111 In-labeled granulocyte migration into affected joints. There was a simultaneous and significant reduction in the numbers of infiltrating synovial CD3 T cells, CD22 B cells, and CD68 macrophages and in the expression of IL-8 and MCP-1, with a trend toward a reduction in serum concentrations of these chemokines. Conclusion. TNF blockade reduces synovial expression of the chemokines IL-8 and MCP-1 and diminishes inflammatory cell migration into RA joints.

OBJECTIVE.The purpose of this study was to determine the effects of percutaneous transcatheter coil embolization of pulmonary arteriovenous malformations on arterial oxygen saturation, pulmonary gas exchange, anatomic right-to-left shunt, and lung function and to assess the complications of the procedure.

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RationaleAcute respiratory distress syndrome (ARDS) affects over 200 000 people annually in the USA. Despite causing severe, and often refractory, hypoxaemia, the high mortality and long-term morbidity of ARDS results mainly from extra-pulmonary organ failure; however the mechanism for this organ crosstalk has not been determined.MethodsUsing autologous radiolabelled neutrophils we investigated the pulmonary transit of primed and unprimed neutrophils in humans. Flow cytometry of whole blood samples was used to assess transpulmonary neutrophil priming gradients in patients with ARDS, sepsis and perioperative controls.Main resultsUnprimed neutrophils passed through the lungs with a transit time of 14.2 s, only 2.3 s slower than erythrocytes, and with <5% first-pass retention. Over 97% of neutrophils primed ex vivo with granulocyte macrophage colony-stimulating factor were retained on first pass, with 48% still remaining in the lungs at 40 min. Neutrophils exposed to platelet-activating factor were initially retained but subsequently released such that only 14% remained in the lungs at 40 min. Significant transpulmonary gradients of neutrophil CD62L cell surface expression were observed in ARDS compared with perioperative controls and patients with sepsis.ConclusionsWe demonstrated minimal delay and retention of unprimed neutrophils transiting the healthy human pulmonary vasculature, but marked retention of primed neutrophils; these latter cells then ‘deprime’ and are re-released into the systemic circulation. Further, we show that this physiological depriming mechanism may fail in patients with ARDS, resulting in increased numbers of primed neutrophils within the systemic circulation. This identifies a potential mechanism for the remote organ damage observed in patients with ARDS.

Axillary surgery for breast cancer partially obstructs lymph outflow from the arm, chronically raising the lymphatic smooth muscle afterload. This may lead to pump failure, as in hypertensive cardiac failure, and could explain features of breast cancer treatment-related lymphoedema (BCRL) such as its delayed onset. A new method was developed to measure human lymphatic contractility non-invasively and test the hypothesis of contractile impairment.99m Tc-human IgG (Tc-HIG), injected into the hand dermis, drained into the arm lymphatic system which was imaged using a gamma-camera. Lymph transit time from hand to axilla, t transit , was 9.6 ± 7.2 min (mean ± S.D.) (velocity 8.9 cm min −1 ) in seven normal subjects. To assess lymphatic contractility, a sphygmomanometer cuff around the upper arm was inflated to 60 mmHg (P cuff ) before 99m Tc-HIG injection and maintained for >> t transit . When P cuff exceeded the maximum pressure generated by the lymphatic pump (P pump ), radiolabelled lymph was held up at the distal cuff border. P cuff was then lowered in 10 mmHg steps until 99m Tc-HIG began to flow under the cuff to the axilla, indicating P pump ≥ P cuff . In 16 normal subjects P pump was 39 ± 14 mmHg. P pump was 38% lower in 16 women with BCRL, namely 24 ± 19 mmHg (P = 0.014, Student's unpaired t test), and correlated negatively with the degree of swelling (12-56%). Blood radiolabel accumulation proved an unreliable measure of lymphatic pump function. Lymphatic congestion lymphoscintigraphy thus provided a quantitative measure of human lymphatic contractility without surgical cut-down, and the results supported the hypothesis of lymphatic pump failure in BCRL.

The kinetics of human autologous granulocytes, separated and labelled with 111In without isolation from plasma, have been studied in subjects with and without sepsis with the aim of identifying the fate and sites of destruction of granulocytes in man. In subjects without inflammatory disease, 111In granulocyte recovery in faeces, urine and saliva over 4 d was less than 1% of the dose, so that the activity visualized by the gamma camera represented almost 100% of the dose. On images taken at 24 and 48 h, this activity was distributed between spleen, bone marrow and liver, with foci of additional abnormal activity in subjects with inflammatory disease. Splenic activity fell between 40 min and 24 h, consistent with the presence of a splenic granulocyte pool, but remained constant after 24 h. Since granulocyte clearance from the blood was predominantly completed by 24 h, the residual splenic activity at that time reflected splenic granulocyte destruction. In patients with sepsis, the fall in splenic activity was greater than in those without, implying diversion of granulocytes from splenic destruction to tissue utilization when inflammation is present. Bone marrow activity increased between 40 min and 24 h and then remained stable. Granulocytes that were extensively manipulated in saline prior to labelling failed to localize in marrow, suggesting that visualization of the latter reflected destruction of intact, normal granulocytes. Although the changes in splenic and marrow activities terminated at 24 h, at which time granulocyte clearance from blood was at least 80% completed, plasma 111In remained essentially unchanged between 40 min and 48 h at less than 5% of the dose, discounting it as the source of splenic and marrow activities.

Glomerular filtration rate (GFR) is routinely calculated from the second exponential of the bi-exponential plasma clearance of filtration markers such as Cr-51 EDTA and Tc-99m DTPA. By ignoring the first exponential, true GFR is overestimated, an error which increases with increasing GFR. The rate constant, lambda 2, of the second exponential represents the rate at which glomerular filtration 'turns over' the extracellular fluid (ECF) and so closely approximates GFR/ECF volume. Again, the error in the estimation of this ratio increases with increasing GFR, although in this case it underestimates the true ratio. Expressing GFR in terms of ECF volume, rather than in terms of body surface area, offers considerable technical and physiological advantages. The relationship between GFR/ECF volume and lambda 2, over a wide range of renal function, expressed as a second order polynomial, was GFR/ECF volume = -0.093 + 1.06 lambda 2 + 0.009 lambda 2(2) ml.min-1.l-1. The corresponding relationship between 'true' GFR (C1) and approximate GFR (i.e. based only on the second exponential--C2) was C1 = -0.58 + 1.012C2 -0.0011 C2(2) ml.min-1 For any level of renal function, the error in GFR/ECF volume, expressed as lambda 2, is less than the error in GFR expressed as C2. Since GFR may change as a direct result of a change in ECF volume, it is physiologically more relevant, and technically very much easier, to express GFR in terms of ECF volume rather than body surface area.